Direct Radical C 1 Homologations

Abstract

Radical reactions have an important place in organic synthesis, as they often allow for surprisingly mild and selective transformations. C 2 homologations can be achieved routinely through addition to CC double bonds, which is one of the classical radical reactions. C 1 homologations on the other hand are much rarer, but two general principles emerged, which are discussed in this chapter. (i) Simple introduction of methylene or carbonyl groups can be achieved through addition to CX π-bonds. (ii) Branched systems only became accessible much more recently through oxidation triggered 1,2-rearrangements of α-boryl radical ate -complexes. As both concepts thus complement each other synthetically, they are discussed based on selected examples from the literature, as well as computational data for their key intermediates. The addition to CX double bonds only has a relatively low thermodynamic driving force (especially for CO), but nevertheless hydroxymethylation, aminomethylation, and alkoxyaminomethylation reactions have been reported. Carbon monoxide can be considered a geminal radical acceptor, and radical additions yielding formylation and acylation products have been realized successfully. The low thermodynamic driving force means that additions are often reversible, and reactivity patterns are controlled kinetically. Thus, substituents at the newly introduced carbon atom are counterproductive, and branched products remain somewhat elusive. α-Boryl radicals on the other hand benefit from the additional stabilization alkyl substituents provide. This allows for the introduction of (di)substituted C 1 units. Both free boronate esters and their ate -complexes stabilize α-boryl radicals to a certain extent. Kinetically, however, there is a stark difference. The electron-rich ate -complexes are preferably attacked by electrophilic radicals, leading to nucleophilic (and thus readily oxidized) α-boryl radicals. The corresponding free Lewis acids on the other hand are more electron-deficient, and thus they, as well as the corresponding α-boryl radicals, are somewhat amphiphilic in their nature. α-Boryl radicals were created by both hydrogen atom transfer (HAT) and atom transfer radical addition (ATRA) to alkenes and strained cyclic systems. Oxidation of the radical ate -complexes with electrophilic halogenates triggered 1,2-rearrangement and thus CB bond insertion, which preferably yielded branched products. Thus both types of radical homologations complement each other, as well as their polar counterparts to which they are compared.